Project Summary/Abstract: This proposal describes a five-year research and career development plan intended to support the applicant's progression to an independent physician scientist investigating the intersection between resident immune cell communication via extracellular vesicles (EVs) and host defense against a pulmonary pathogen. Research plan: Influenza is a significant health and economic problem in the US. Vaccination is incompletely effective and available treatments have limited efficacy. Morbidity and mortality from infection occur when the influenza virus spreads to the distal alveolar airspaces, compromising gas exchange. Host and environmental factors alter susceptibility to infection through incompletely understood mechanisms. Understanding alveolar host defense mechanisms against infection could lead to the development of effective therapeutics and improved vaccination strategies. The applicant has discovered that resident macrophages inhibit influenza infection within alveolar epithelial cells through the release and delivery of anti-viral activity within EVs. In this proposal, the applicant will investigate the steps of the influenza replication cycle targeted by these EVs, define protein constituents within EVs responsible for this anti-viral activity, and describe how cigarette smoke alters the constituents of these EVs to modulate their activity. Applicant: The applicant holds M.D. and Ph.D. degrees and has completed clinical training in Internal Medicine, Pulmonary, and Critical Care Medicine. He has previous experience with mouse models and in vitro systems to study normal lung physiology and non-infectious pathology. The career development plan includes mentored research designed to develop new knowledge and techniques in virology, proteomics, bioinformatics, and mouse models of viral infection. Acquiring skills and experience in these new areas will greatly facilitate his development into an independent investigator studying the mechanisms by which EVs mediate host defense against respiratory pathogens. Training in these areas will be acquired under the guidance of his experienced mentoring team, and through participation in seminars, lab meetings, coursework, workshops, and national meetings. He will also receive training in grant writing and responsible conduct of research. The outstanding institutional research environment affords ample intellectual interactions with investigators in virology, immunology, proteomics, and bioinformatics as well as basic and clinical/translational scientists. Facilities for advanced imaging, gene expression, immunophenotyping, and differential protein characterization are available. This application will thus enable a highly trained and committed junior investigator to develop an independent career in the investigation of a new host communication paradigm applied to defense against respiratory infections.